BioMed Central
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Journal of Ovarian Research
Open Access
Review
Emerging role of microRNAs in diagnosis and treatment of various
diseases including ovarian cancer
Parag P Shah, Lauren E Hutchinson and Sham S Kakar*
Address: Department of Physiology and Biophysics, James Graham Brown Cancer Center, University of Louisville, Louisville. KY 40202, USA
Email: Parag P Shah - ; Lauren E Hutchinson - ;
Sham S Kakar* -
* Corresponding author
Abstract
MicroRNAs (miRNAs) represent a class of small non-coding RNAs that control gene expression
by targeting messenger RNA (mRNA). Recently, it has been demonstrated that miRNA expression
is altered in many human diseases including cancers, suggesting that miRNA may play a potential
role in the pathogenesis of different diseases. It has also been reported that there is a unique
expression pattern of miRNAs in the disease state differing from the normal state. In this review,
we focus on the miRNA signatures in different human diseases including cancers. Such signatures
may be used as diagnostic and prognostic markers.
Discovery of microRNA
Discovered in 1993 from nematode Caenorhabditis elegans,
miRNA are small, non-coding RNAs composed of 18–24
nucleotides. They act by negatively regulating gene expres-
sion at the post-transcriptional level through modulation
of mRNA expression. Lee et al. [1] found that lin-4, an
important gene that is important for post-embryonic
development of C. elegans, does not code for a protein.
Instead, it is transcribed into a 22-nucleotide RNA mole-
cule. Seven years later, a second miRNA, let-7, also

Published: 27 August 2009
Journal of Ovarian Research 2009, 2:11 doi:10.1186/1757-2215-2-11
Received: 27 July 2009
Accepted: 27 August 2009
This article is available from: />© 2009 Shah et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( />),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Journal of Ovarian Research 2009, 2:11 />Page 2 of 9
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as various forms of cancers, lymphomas, diabetes and
neurological disorders such as Parkinson's and Alzhe-
imer's diseases. Recently, there has been considerable
interest in understanding the mechanism of the RNA reg-
ulatory phenomena and how miRNA functions in car-
cinogenesis. Specifically, determining how the regulation
of miRNA may be targeted to develop cancer therapies has
been a focus. In this review, we discuss recent discoveries
related to miRNA in different cancer diagnoses and, in
particular, treatment related to ovarian cancer (OVCA).
Biogenesis of miRNA
Like proteins, miRNAs are transcribed from DNA into a
primary (Pri) RNA transcript. In the first step, formation
of Pri-miRNA inside the nucleus occurs from the tran-
scription of the miRNA gene by RNA polII. The Pri-
miRNA is capped, polyadenylated, and then processed by
RNAase III endonuclease Drosha and the double stranded
(ds) RNA-binding protein Pasha. This processing results
in the formation of a 60 to 70 nucleotide stem loop pre-
cursor (Pre) called Pre-miRNA. The Pre-miRNA is then
transported to the cytoplasm by the Ras-related nuclear

ease, gene mutations can result in inherited forms of
Parkinson's disease [7]. Kim et al. [8] suggest that miRNAs
are essential for maintaining the dopaminergic neurons in
the brain. Given that Parkinson's disease is characterized
by an extreme loss of dopaminergic neurons, it could be
possible that miRNAs play a role in the disease pathogen-
esis. These investigators [8] hypothesized that inducing
alterations in the miRNA networks of the brain results in
neurodegenerative disorders to some extent. Based on the
results of this study and from information obtained in
previous work performed with mice [9], flies [10] and cul-
tured neurons [8] in which the enzyme Dicer was geneti-
cally inactivated, Kim et al. [8] concluded that loss of
Dicer results in complete inactivation of miRNA and is tre-
mendously detrimental [11]. Moreover, Dicer was shown
to be important for neuronal survival, as the loss of miR-
NAs may result in development and/or progression of
Parkinson's disease [8,9].
Spinal muscular atrophy (SMA) is a common genetic dis-
ease characterized by the progressive degeneration of
motor neurons. It has been demonstrated that deletion or
loss-of-function mutations in the survival of motor neu-
ron (SMN) protein results in SMA [12]. Gemin 3 and
Gemin 4 are shared components of SMN and miRNA-
containing ribonucleoprotein particles (miRNPs). Dele-
tion or loss-of-function mutations of SMN in SMA may
affect the activity of miRNPs due to possible redistribu-
tion or changes in the levels of Gemin 3 and 4.
Using RNA immunoprecipitation 3'-end labeling and
miRNA cloning, Dostie and colleagues [13] identified 53

hemodynamic overload, endocrine disorders, myocardial
injury, or inherited mutations in the various structural
and contractile proteins [15]. Multiple genes are aber-
rantly expressed in hypertrophic cardiac cells. Using
microarray analysis, miRNA expression pattern in hearts
revealed that miR-1, miR-29, miR-30, miR-133, and miR-
150 have often been found to be down-regulated while
miR-21, miR-125, miR-195, miR-199, and miR-214 are
up-regulated with hypertrophy.
MiR-21 is found to be consistently induced by cardiac
stress and appears to function as a regulator of cardiac
growth and fetal gene activation in primary cardiomyo-
cytes in vitro. Its role in myocyte hypertrophy was demon-
strated by Cheng et al. in 2007 [16]. Their study showed
that knockout of miR-21 by an inhibitor suppresses cardi-
omyocyte hypertrophy induced by angiotensin II in cell
culture experiments [16]. This indicates that overexpres-
sion of miR-21 has a functional role in cardiac hypertro-
phy. Tatsuguchi et al. [17] also confirmed the role of miR-
21 in cardiac hypertrophy using locked nucleic acid mod-
ified oligos. Recently, Sayed et al. [18] reported that miR-
21 modulates the cellular outgrowths during hypertrophy
through the regulation of sprouty 2, an intracellular
inhibitor of mitogen-activated protein-kinase signaling.
Another miRNA that is consistently up regulated in rodent
and human hypertrophic hearts is miR-195. Forced
expression of miRNA-195 in transgenic mice is sufficient
to induce hypertrophic growth and also results in dilated
cardiomyopathy and heart failure [19].
MiR-208 is encoded within intron 27 of the α major his-

insulin secretion, making miR-375 an important modula-
tor of β-cell function. Keller et al. [23] suggested the addi-
tional targets of miR-375 could be the pancreatic
transcription factors pdx-1 and NeuroD1. This indicates
that miR-375 may play important role in interacting with
transcription factors that control pancreatic maintenance
and development [24].
MiRNA and carcinogenesis
Recent studies show that several miRNAs are differentially
expressed in several human cancers, which indicate that
miRNAs may have a role in the carcinogenic processes
(See Table 1). In 2002, Calin et al. [25] correlated aberrant
miRNA expression with cancer. The first study that was
reported regarding the abnormalities in miRNA expres-
sion was in miR-15a and miR-16-1 in B-cell chronic lym-
phocytic leukemia (CLL); [25]. The study showed that
miRNA 15 and miRNA 16 genes are located in a deleted
region present in more than half of B-cell CLL cases and
that both of the genes are deleted/mutated in more than
half of the in CLL cases. In addition, miR-17-92, which is
present as a cluster of miRNAs on chromosome 13, was
reported to be associated with B cell lymphoma [26].
Journal of Ovarian Research 2009, 2:11 />Page 4 of 9
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Table 1: Differentially expressed miRNAs in various cancers.
miRNAs Cancer types Reference
mir-17-92 cluster β-cell lymphoma lung carcinoma Hayashita et al. (2005) [36]
lung carcinoma Hayashita et al. (2005) [36]
miR-145 colon, breast, lung and Prostate Cummins et al. (2006) [47]
Akao et al. (2006) [48]

miR-17-5p Bladder and Lung Gottardo et al. (2007) [58]
Matsubara et al. (2007) [66]
miR-34a Ovary, Lymphocytic Iorio et al. (2007) [4]
leukemia Zanette et al. (2007) [67]
miR-200c Ovary Iorio et al. (2007) [4]
miR-23a Lung Yanaihara et al. (2006) [50]
Journal of Ovarian Research 2009, 2:11 />Page 5 of 9
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Other miRNAs that have been discovered to be abnor-
mally expressed in cancerous tissues include: miR-145,
which is down regulated in breast cancer [27] ovarian can-
cer [4]; miR-10b, which is found to be mostly down regu-
lated in breast cancer [27]; and miR-145, which has
reduced expression in colorectal cancer [28].
MiRNAs participate in various biological processes
including cell differentiation, proliferation, apoptosis,
stress resistance, and fat metabolism [29] and often have
dual functions. For instance, in some types of cancers,
they possess oncogenic activity, while in others they can
suppress tumor development. Michael et al. [28] showed
that miR-143 and mi-R-145 have been associated with the
reduction of some malignancies, suggesting their poten-
tial tumor suppressing activities. Additional studies dem-
onstrated that miRNAs were found to suppress BCL2, an
anti-apoptotic gene [30]; supporting the idea that miRNA
can also have oncogenic activity. Furthermore, miR-372
and miR-373 cooperate with oncogenic Ras in the cellular
transformation of testicular germ cell tumors [31]. Addi-
tionally, in the Let-7 family, Let 7a-2 and Let 7a-3 are
down regulated in lung cancer and Ras is frequently

ues to be the leading cause of death resulting from gyne-
cological malignancies [39]. Histologically, OVCA is
divided into different subgroups such as serous, muci-
nous, endometrioid, clear cell, Brenner, and undifferenti-
ated carcinomas [40]. The high mortality rate of this
disease is due to late stage diagnosis for more than 70% of
affected patients (Chemoresistance). Trans-vaginal ultra-
sound and serum CA-125 remain poor tests for diagnos-
ing the disease in its early stage and, as a result, most cases
are still more likely to be detected at the advanced stage
[41].
New, more effective diagnostic tests must be developed to
identify OVCA in its early stage. If OVCA is diagnosed in
the early stage, current treatments will be more successful,
which in turn will significantly reduce the high mortality
rate. The discovery that miRNAs are expressed at different
levels in normal versus malignant tissues offers the possi-
bility of identifying new methods of diagnosing early
stage incidence and discovering new therapies for the
treatment of OVCA.
With the advent of new miRNA technology, it is possible
to plan appropriate treatments and predict chemotherapy
outcomes. Studies have shown that miRNAs, which are
noncoding regulatory RNA products, are aberrantly
expressed in many cancer types including breast [27], pan-
creatic [42], and lung cancer [4]. In addition to these
forms, a study conducted by Iorio et al. in 2007, [4] con-
firmed that miRNAs are also abnormally expressed in
OVCA (See Table 2). It was concluded that in the cancer-
ous tissues, i.e., miR-141, miR-200a, miR-200b, and miR-

that a patient's serum miRNA level could be used to
potentially diagnose OVCA. Additionally, miRNAs 21, 92,
and 93 were also overexpressed in patients with normal
CA125 levels. This suggests that earlier diagnosis of OVCA
may be possible through the identification of these miR-
NAs even though patients may present with normal CA-
125 levels [43].
Another new non-invasive method with the potential for
diagnosing OVCA involves isolating tumor-derived exo-
somes. Exosomes are saucer shaped nanovesicles (30–100
nm) that are normally released by multiple mammalian
cell types and have a significant role in cell-to-cell com-
munication. In addition to exosomes released by normal
proliferating cells, tumor cells also release exosomes.
Tumor cells release exosomes at a much higher level than
normal cells and the exosomes also display numerous
tumor antigens that mirror the primary tumor cells. There-
fore, it is proposed that these tumor-derived exosomes
could be used as a diagnostic biomarker. In addition to
the antigens, circulating tumor-derived exosomes have
been shown to contain miRNAs that parallel those of the
original tumor [44]. This demonstrates that miRNA profil-
ing can be executed and accurately represent the originat-
ing tumor through a blood sample rather than requiring
the more invasive tissue sample. It has been shown that
eight particular miRNAs are of diagnostic significance in
OVCA. MiRNA 21, 141, 200a, 200b, 200c, 203, 205, and
214 are all overexpressed in tumor cells and tumor-
derived exosomes. The levels are different enough to
clearly distinguish between benign and malignant tumors

miRNAs Up/Down-regulated Reference
miR-21, miR-92, miR-93, miR-126, miR-29a up-regulated Resnick et al., 2009[43]
miR-155, miR-127, miR-99b down-regulated Resnick et al., 2009[43]
miR-200a, miR-141, miR-200c, miR-200b up-regulated Iorio et al., 2007[4]
Zhang et al., 2006 [39]
miR-199a, miR-140, miR-145, miR-125b1 down-regulated Iorio et al., 2007 [4]
Zhang et al., 2006 [39]
miR-100, miR-199a, miR-295, miR-29a, miR-29c, miR-99a, miR-494 up-regulated Dahiya et al., 2008 [68]
Kerscher et al., 2006 [2]
let-7d, miR-106b, miR-122a, miR-141, miR-183, miR-195, miR-200a, miR-335, miR-424, miR-155,
miR-488, let-7a
down-regulated Dahiya et al., 2008 [68]
Iorio et al., 2007 [4]
Zhang et al., 2006 [39]
Journal of Ovarian Research 2009, 2:11 />Page 7 of 9
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mechanism behind regulating miRNA expression is deter-
mined. Then, for instance, miR-378, which is down-regu-
lated in malignant ovarian tissue, could be induced to
over express to a normal level, possibly making the cells
more sensitive to platinum-based chemotherapy. Moreo-
ver, identification of specific miRNAs between types of
cancers (lung, ovarian, pancreatic) and even within types
(endometrioid, clear cell, serious in ovarian) could allow
for more personalized treatments, which certainly present
the chance for a better prognosis.
While there is not much information currently available
on the mechanisms responsible for inducing aberrant
miRNA expression, there is a new possible explanation for
their overexpression in OVCA. Iorio et al. [4] recently

stranded miRNA; (miRISC): miRNA-associated multipro-
tein RISC; (SMA): Spinal muscularatrophy; (SMN): sur-
vival of motor neuron; (miRNP): miRNA-
containingribonucleoprotein particle; (ban): bantam;
(polyQ): polyglutamine; (SCA 3): spinocerebellar ataxia
type 3; (MHC): major histocompatibility complex; (TR):
thyroid-hormone-receptor; (THRAP1): thyroid-hormone-
receptor co-regulator TR-associated protein 1; (CLL):
chronic lymphocytic leukemia; (EOC): Epithelial ovarian
cancer; (OVCA): ovarian cancer.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
PPS drafted the manuscript. LEH contributed in writing
part of the manuscript. SSK conceptualized, edited, and
revised the manuscript. All authors have read and
approved the final manuscript.
Additional material
Acknowledgements
The authors thank Mr. Andrew Marsh for critical editing of the manuscript.
This work was supported by a grant from NIH/NCI 124630 (SSK).
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